Thierry Bussiere

The antibody aducanumab reduces Aβ plaques in Alzheimer's disease.

Alzheimer’s disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating—Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

Morphological characterization of thioflavin-s-positive amyloid plaques in transgenic Alzheimer mice and effect of passive Aβ immunotherapy on their clearance

Transgenic mice mimicking certain features of Alzheimers disease (AD)-pathology, namely amyloid plaques and neurofibrillary tangles, have been developed in an effort to better understand the mechanism leading to the formation of these characteristic cerebral lesions. More recently, these animal models have been widely used to investigate emergent therapies aimed at the reduction of the cerebral amyloid load. Several studies have shown that immunotherapy targeting the amyloid peptide (Abeta) is efficacious at clearing the amyloid plaques or preventing their formation, and at reducing the memory/behavior impairment observed in these animals. In AD, different types of plaques likely have different pathogenic significance, and further characterization of plaque pathology in the PDAPP transgenic mice would enhance the evaluation of potential therapeutics. In the present study, a morphological classification of amyloid plaques present in the brains of PDAPP mice was established by using Thioflavin-S staining. Neuritic dystrophy associated with amyloid plaques was also investigated. Finally, the efficacy of passive immunization with anti-Abeta antibodies on the clearance of Thio-S positive amyloid plaques was studied. Our results show that distinct morphological types of plaques are differentially cleared depending upon the isotype of the antibody.

Immunotherapy with Aducanumab Restores Calcium Homeostasis in Tg2576 Mice

Calcium homeostasis plays a major role in maintaining neuronal function under physiological conditions. Amyloid-β (Aβ) initiates pathological processes that include disruption in intracellular calcium levels, so amelioration of the calcium alteration could serve as an indirect functional indicator of treatment efficacy. Therefore, calcium dynamics were used as a measure of functional outcome. We evaluated the effects of the anti-Aβ antibody aducanumab on calcium homeostasis and plaque clearance in aged Tg2576 mice with in vivo multiphoton imaging. Acute topical application of aducanumab to the brain resulted in clearance of amyloid plaques. Although chronic systemic administration of aducanumab in 22-month-old mice did not clear existing plaques, calcium overload was ameliorated over time. Therefore, this antibody likely restores neuronal network function that possibly underlies cognitive deficits, indicating promise as a clinical treatment. In addition, functional readouts such as calcium overload may be a more useful outcome measure to monitor treatment efficacy in models of Alzheimers disease compared with amyloid burden alone. SIGNIFICANCE STATEMENT Alzheimers disease (AD) is a progressive neurodegenerative disorder that is currently without a cure. Aducanumab is an anti-amyloid-β antibody being developed for the treatment of AD. Interim analyses of a phase 1b clinical trial have suggested potential beneficial effects on amyloid pathology and cognitive status in patients treated with aducanumab (Sevigny et al., 2016). Here, we show that a murine analog of aducanumab clears amyloid plaques in an acute setting and restores calcium homeostasis disrupted in a mouse model of AD upon chronic treatment. Therefore, we demonstrate that aducanumab reverses a functional outcome measure reflective of neural network activity.

Molecular characterization and preclinical efficacy

Background: Passive immunotherapy with anti-Abeta antibodies is currently investigated for the treatment of Alzheimer’s Disease with several candidates in preclinical or clinical development. Methods: BIIB037 was generated using the Reverse Translational Medicine method (RTM). Binding properties of BIIB037 were measured in vitro against soluble and fibrillar Abeta. In vivo studies using Tg2576 mice were conducted to assess brain penetration and binding to amyloid plaques, as well as PK profile of the antibody. Preclinical efficacy was determined after chronic dosing using biochemical and histopathological endpoints. Results: BIIB037 is a fully human IgG1 monoclonal antibody derived from an AD patient with an unusual stable clinical course. The RTM approach was used to isolate, clone and recombinantly express the antibody. In vitro characterization shows a high affinity for insoluble fibrillar human Abeta using an ELISA format assay with fibrillar Abeta1-42 immobilized on the plate, and BIIB037 doesn’t bind to soluble Abeta1-40 in an inverted ELISA assay format. Binding was also evaluated using a TAPIR assay and staining of amyloid plaques in both AD brain and transgenic mice brain tissues was observed. BIIB037 enters the brain and binds to amyloid plaques after systemic administration in Tg2576 transgenic mice. The amount of drug detected into the brain is dosedependent. Chronic dosing for 6 months led to a significant amyloid load reduction as measured by ELISA and histopathology, but didn’t lead to increased plasma Abeta1-40, Abeta1-42 levels. Incidence of microhemorrhage and inflammation was not increased compared to vehicle treated group.Conclusions:A novel fully human antibody recognizing fibrillar human Abeta was characterized and its preclinical efficacy was demonstrated in vivo.

Addendum: The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease

This corrects the article DOI: 10.1038/nature21361

Quantitation of beta-amyloid in transgenic mice using whole slide digital imaging and image analysis software

the naturalhistory of small vessel diseases, evaluated in a large cohort of postmortem brains from the Newcastle Institute for Ageing and Health (Newcastle University, UK). This provides a score from 0 to 20 (no to severe vascular burden) and is in good agreement previous neuropathological standards. Nevertheless, the clinical relevance of this score has not yet been evaluated, and this was this study’s aim. Methods: Post mortem AD brains from Lille Neurobank (Lille, France) were scored according this cerebrovascular scale, blinded to clinical and neuroimaging data. Patients had been prospectively followed up with a standardized clinical examination, neuropsychological tests, and structural brain imaging. Correlation with the clinical diagnosis of vascular contribution, age at onset, disease duration, imaging white matter lesions visual scoring scale (Fazekas et al. 1987), vascular risk factors, Mini Mental State Examination score and Dementia Rating Scale score at first visit were analyzed with non-parametric tests. Results: Eleven patients were included. Four of them had a neuropathological cerebrovascular score < 10, all these 4 patients were clinically diagnosed as pure AD. Six of the 7 patients with a score 1⁄4 10 were considered to have no significant cerebrovascular contribution to their dementia. Higher scores were associated with a longer disease duration (p1⁄4 0.05) andtended to be associated with a higher Fazekas score.Conclusions: There is an urgent need to establish a reproducible and standardized quantitative assessment of the cerebrovascular burden in post mortem brains. In this small study, we used an original neuropathological cerebrovascular staging system which seems to be relevant enough to identify the clinical and imaging correlates of the cerebrovascular burden in clinicopathological series. In this limited number of cases, the clinical contribution of cerebrovascular lesions was largely underestimated. Further inclusions are needed to confirm our findings.